Short interfering RNA therapy dramatically lowers Lp(a) in phase 1 trial

WASHINGTON — In the phase 1 APOLLO study, a short interfering RNA therapy lowered lipoprotein(a) by a maximum of more than 90% in certain doses, researchers reported at the American College of Cardiology Scientific Session.

The agent, SLN360 (Silence Therapeutics), is one of several in development to reduce Lp(a), elevated levels of which are a major CVD risk factor and are not effectively treated by existing therapies.

Steven E. Nissen

“There are no approved therapies for treating lipoprotein(a); it’s kind of the last frontier,” Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, who presented the data, told Healio. “There are three in development, all with different approaches. There is extremely strong evidence from Mendelian randomization studies and epidemiological studies that Lp(a) is a very powerful risk factor for both atherosclerotic CVD and aortic stenosis. It’s not been treatable; everything we [have tried] has minimal effects, if any at all. It’s a pure genetic risk factor. Tea LPA gene makes messenger RNA, which then makes apolipoprotein A, which then forms lipoprotein(a) particles. The only way to approach the disease is to silence the gene. This agent is a small snippet of double-stranded RNA that’s connected to a sugar called N-acetylgalactosamine (GalNAc). The liver takes up the GalNAc and cleaves it, and there is now interfering RNA in the hepatocytes in the liver, where it combines with messenger RNA and degrades it, which means it does not make apolipoprotein A or lipoprotein(a).”

The researchers randomly assigned 32 adults with Lp(a) plasma concentrations of at least 150 nmol/L (mean age, 50 years; 53% women) to a single dose of placebo or SLN360 at one of the following doses: 30 mg, 100 mg, 300mg or 600mg. Participants had follow-up visits at 7, 14, 30, 45, 60, 90 and 150 days after dosing.

The main purpose of the study was to assess safety and tolerability. One participant reported two serious adverse events, neither of which were deemed to be related to the study drug.

“You can’t really establish safety with 32 patients, so there is lots of work left to be done before this will go into large phase 3 trials, but nonetheless, we see the results as promising,” Nissen told Healio.

Reductions in Lp(a)

The maximal median changes in Lp(a) were –20 nmol/L (interquartile range [IQR]–61 to 3) in the placebo group, –89 nmol/L (IQR, –119 to –61) in the 30 mg group, –185 nmol/L (IQR, –226 to –163) in the 100 mg group , –268 nmol/L (IQR, –292 to –189) in the 300 mg group and –227 nmol/L (IQR, –270 to –174) in the 600 mg group, according to the researchers.

Nissen said the maximal median percentage changes in Lp(a) were as follows:

• placebo group, –10% (IQR, –16 to 1);
• 30 mg group, –46% (IQR, –64 to –40);
• 100 mg group, –86% (IQR, –92 to –82);
• 300 mg group, –96% (IQR, –98 to –89); and
• 600 mg group, –98% (IQR, –98 to –97).

The 96% reduction observed in the 300 mg group occurred on the day 45 visit and the 98% reduction observed in the 600 mg group occurred on the day 60 visit, and at 150 days, the 300 mg group had a 71% reduction, and the 600 mg group had an 81% reduction, Nissen said during a presentation.

“Considering that this is a disease for which we have no treatments, it is clearly a step forward,” Nissen told Healio. “This may offer some hope for patients whom we have been unable to treat. They may have MI as early as in their 40s or premature aortic stenosis. All we have been able to tell them is we can modify their other risk factors and hope for the best. I am looking forward to the day when we have a very specific treatment.”

SLN360 also produced a dose-dependent reduction in LDL and total cholesterol, with a maximal 26% reduction in LDL and 18% reduction in total cholesterol conferred by the 600 mg dose, according to the researchers.

In addition, Nissen said, the maximal reductions in apolipoprotein B were 21% in the 300 mg group, observed on day 45, and 24% in the 600 mg group, observed on day 60.

A multi-dose trial is now underway and development is “moving stepwise really quickly toward the later-phase trials,” Nissen told Healio.

The study was simultaneously published in JAMA.

CV outcome trials needed

Brian A. Ference

In a related editorial in JAMA, Brian A. Ference, MD, MPhil, MSc, FACC, CSCF, director of research (professor) in translational therapeutics and executive director of the Center for Naturally Randomized Trials at the University of Cambridge, UK, wrote: “Because of the uncertainty about the magnitude of Lp(a) lowering needed to reduce the risk of cardiovascular events, it is important to continue to evaluate the safety and efficacy of the small interfering RNA in the study reported by Nissen and colleagues as well as a similar small interfering RNA in development. A series of cardiovascular outcome trials evaluating multiple different antisense oligonucleotide and small interfering RNA therapies will provide the most robust estimate of the clinical benefit of lowering Lp(a) and help identify which individuals are likely to benefit most from lowering Lp(a).”

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Dipti Itchhaporia, MD, FACC, FESC

Lp(a) is involved with atherosclerosis, and we really have not had any treatment for it. This agent was tried in several different dosages to see if it was safe and if it impacted Lp(a). The small study of 32 patients showed it was safe and effective. Obviously, we will need more data, but the results are exciting because this is an area for which we have no treatment.

Dipti Itchhaporia, MD, FACC, FESC

Eric & Sheila Samson Endowed Chair in Cardiovascular Health

Director of Disease Management

Jeffrey M. Carlton Heart and Vascular Institute

Hoag Memorial Hospital, Newport Beach, California

Assistant Clinical Professor of Medicine

University of California, Irvine

President, American College of Cardiology

Cardiology Today Editorial Board Member

Disclosures: Itchhaporia reports no relevant financial disclosures.

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